The overall objective of this application for a Specialized Center of Clinical Research is to investigate novel aspects of the pathogenesis and treatment of acute lung injury in humans. Acute lung injury is an important clinical problem in critically ill patients that affects more than 100,000 patients annually in the United States. Our major hypothesis is that new advances in understanding pathogenesis and treatment will come from research approaches that take into account the complexity of biological responses in humans. Past approaches to this disease have emphasized single pathways in pathogenesis and treatment, but recent developments in biotechnology have made it possible to approach lung injury from a systems point of view that recognizes the importance of multiple pathways in the injury and repair process. Our application brings together a cohesive group of six projects (three clinical and three basic) and three cores, Administrative, Biotechnology, and Educational. Project 1 will investigate the complexity of host determinants of inflammatory responses in normal and critically ill patients; Project 2 will perform a randomized trial of a new treatment program in survivors of acute lung injury, recognizing the complex clinical needs of these patients; Project 3 will perform pilot projects of new treatments with the aim of taking forward positive results to larger clinical trials; Project 4 investigates the complex early interactions between bacteria and the alveolar environment that influence bacterial pathogenesis; Project 5 investigates a novel new pathway that protects mice from systemic sepsis; and Project 6 investigates the complex mechanisms that control alveolar epithelial injury. The proposed studies evolve logically from ongoing studies in the current Seattle ARDS Research Program. The proposed SCCOR Program will enhance understanding of the pathogenesis of lung injury and could lead to new treatments and improved long-term outcome for patients with acute lung injury.